Certain 2-cheterocylic acylimino)-5-nitro-4-thiazoline-3-acetamides

ABSTRACT

5-Nitro-4-thiazoline-3-acetamide compounds having the formula   AND SALTS THEREOF; WHERE R1 is 2-furyl, 2-thienyl, 2-pyridyl, 3pyridyl, or 4-pyridyl, and each of R2 and R3 is hydrogen or an alkyl radical containing not more than three carbon atoms. The compounds are produced by reacting a 5-nitrothiazole with an Alpha -haloacetamide and are useful as schistosomacides and trichomonacides.

United States Patent Islip CERTAIN Z-(HETEROCYCLICACYLIMINO)-5-NITRO-4-THIAZ6LINE 3-ACETAMIDES [72] Inventor: Peter Johnlslip, Hampton, England [73] Assignee: Parke, Davis & Company, Detroit,Mich.

122] Filed: May 14, 1970 [21] Appl. No.: 37,295

[30] Foreign ApplicationPriority Data June 18, 1969 Great Britain..30,950/69 [52] US. Cl. ..260/294.8 D, 260/306.7, 424/266, 424/270 [51Int. Cl. ..C07d 31/50 [58] Field of Search ..260/294.8 D, 306.7 I

[56] References Cited UNlTED STATES PATENTS 3,499,907 3/1970 lslip..260/306.7

[ 5 1 June 20, 1972 3,523,l22 8/1970 Capps ..260/306.7

Primary Examiner-Alan L. Rotman Attorney-Robert R. Adams, David B.Ehrlinger, George M. Richards and Edward J. Gall [5 7] ABSTRACT5-Nitro-4-thiazoline-3-acetamide compounds having the formula 8 Claims,No Drawings CERTAIN Z-(HETEROCYCLIC ACYLIMINO)--NlTRO-4-THIAZOLlNE-3-ACETAMIDES SUMMARY AND DETAILED DESCRIPTION The presentinvention relates to new heterocyclic compounds that are useful aschemotherapeutic agents and to methods for their production. Moreparticularly, the invention relates to new5-nitro-4-thiazoline-S-acetamide compounds having the formula i N 011 l/R and to pharmaceutically-acceptable salts thereof; where R is 2-furyl,2-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, and each of R and R ishydrogen or an alkyl radical containing not more than three carbonatoms.

In accordance with the invention, compounds having formula l areproduced by reacting a S-nitrothiazole compound having the formula N in0 ON NH-iL-Rr 1r with an a-haloacetamide compound the fiiiiifl'f in thepresence of a base; where R,, R and R have the aforementionedsignificance, and X is chlorine, bromine, or iodine, preferably bromine.Bases that may be used in the reaction include alkali metal hydrides,alkali metal amides, and alkali metal alkoxides. The preferred base isan alkali metal hydride, especially sodium hydride. The reaction is bestcarried out in an unreactive solvent medium. With the preferred alkalimetal hydride base, any of a number of anhydrous, non-hydroxylicsolvents may be used, including ethers, such as diethyl ether, dioxane,and tetrahydrofuran; aromatic hydrocarbons, such as benzene and toluene;tertiary amides, such as N,N-dimethylforrnamide andN-methyl-Z-pyrrolidinone; and dimethyl sulfoxide; as well as mixtures ofthese. A preferred solvent is N,N-dimethylformamide. The temperature andduration of the reaction are not critical and may be varied over a widerange, the temperature from 0 Cto 100 C. and the duration from aboutminutes to about 24 hours. In the preferred method for carrying out thereaction, the S-nitrothiazole compound of formula II and the base arefirst mixed together in the chosen solvent, the a-haloacetamide offormula III is then added, and the resulting reaction mixture is stirredfor a period of from about minutes to about 3 hours at a temperature inthe range of 15 Cto C. Equirnolar quantities of reactants and base arenormally employed, although a slight excess of any one is not harmful.To insure completeness of reaction, it may be desirable to use a slightexcess of both the a-haloacetamide and the base.

The a-haloacetamide compounds used as starting materials in theforegoing process can in general be prepared by reacting an a-haloacetylhalide compound having the formula LII with an amine compound having theformula where each of R R and X is as defined earlier, and X is chlorineor bromine. The preparation of the hitherto unknown starting compoundsof formula II is described in detail hereinafter.

The compounds of the invention having formula I, wherein R is 2, 3--, or4-pyridyl, can exist in the free base form or in the form of anacid-addition salt. Pharmaceutically-acceptable acid-addition salts canbe obtained by reacting the chosen pyridyl-substituted compound in freebase form with any of a variety of acids, including hydrochloric,hydrobromic, hydriodic, nitric, sulfuric, phosphoric, sulfamic, acetic,benzenesulfonic, succinic, maleic, and citric acids. The acidadditionsalts and free bases are interconvertible by adjustment of the pH. Theydiffer in certain physical properties, such as solubility, but, ingeneral, are otherwise equivalent for purposes of the invention.

The compounds of the invention are new chemical compounds that areuseful as chemotherapeutic agents, especially as antiparasitic agentsthat are active schistosomacides and trichomonacides. Their activitiescan be demonstrated and quantitatively measured instandard tests againstSchistosoma mansoni and Trichomonas vaginalis.

In the test used to determine schistosomacidal activity, female Stoutmice weighing l3-l 5 grams each are infected intraperitoneally with S.mansoni (Puerto Rican strain) cercariae (from the snail hostAustralorbis glabratus) six weeks prior to treatment. The experimentalgroups usually consist of five to 10 mice, while the sham-dosed controlgroups number 10 to 15 mice per experiment. All of the mice are fedRockland mouse food from the time of infection to autopsy. The testcompounds are administered in the diet or by gavage. Following treatmentfor a measured period, the animals are killed and autopsied, and theactivity of the test compound is evaluated primarily on the basis of thedistribution and number of living and dead worms in the liver, portalveins, and mesenteric veins. This activity is then expressed in terms ofthe percentage of schistosomes found killed after the period oftreatment at a given dosage. level,-which is expressed either as apercentage of the diet or in mg./kg./day when administration is bygavage. The activities of some representative compounds of the presentinvention, as determined by this test procedure, are shown in the tablethat'follows. The compounds in the table are identified by reference toformula I.

SCI-[ISTOSOMACIDAL ACTIVITY Schistosomes Dead at Mouse Diet Compound forNumber of Days 1 a a Z-furyl CH CH /0.25/ l 4 2-furyl C H, C 11 93/0.25/l 4 4-pyridyl C 11 C l-l 72/0.25/7

72/0.0625/7 Z-thienyl CH CH /025] 14 2 -thienyl C,H C,H, 86/0.25l7

The test used to determine trichomonacidal activity is an in vitro testagainst Trichomonas vaginalis. In this test, Kupferbergs medium,containing 250 'y/ml. of sodium penicillin G and streptomycin sulfate,is inoculated with a sufl'lcient number of organisms from a 24-hourKupferberg culture to give 10,000 trichomonades/ml. The resultingmixture (4.5 ml.) is then added to 0.5 ml. of a solution or suspensionof a measured quantity of the test compound in aqueous ethanol inscrew-capped tubes, and the tubes are incubated at 370 C.

for 48 hours. Varied concentrations of the test compound are obtained byserial dilution. After incubation, the effect of the test compound isdetermined by microscopic examination of 0.02 ml. of the testpreparation dispersed under a 22 X 22 mm. coverslip. The number ofviable trichomonads per Howard disc field is recorded, with at least 10fields being counted. The test preparations are also compared withcontrol tubes to which no test compound is added. The test compound israted as follows, according to the percentage of suppression of thenumber of viable organisms; cidal 100%; static- 90 to 99.9 percent;suppressive 50 to 89.9 percent; inactive less than 50 percent. Thetrichomonacidal activities of some representative compounds of thepresent invention, as determined by the foregoing test procedure, areshown in the following table, where the compounds are again identifiedby reference to formula I.

TRICHOMONACIDAL ACTIVITY Compound R, R R Rating (dosage, Y/ml.) Z-furylCH CH cidal (6.25

- static (1.56) Z-furyl C 11 C 11 suppressive (6.25 4-pyridyl C 11 C: H,cidal (6.25) Z-thienyl CH CH cidal (25) static (6.25)

2-thienyl C 11,, C 11,, cidal 25) The invention is illustrated by thefollowing examples.

Example 1 To a stirred solution of 12.0 g. of N-(5nitro-2-thia-zolyl)-2-furamide in 140 ml. of N,N-dimethylformamide is added in portions 2.4 g.of a 50 percent sodium hydride in mineral oil dispersion.2-Bromoacetamide (6.9 g.) is added next, and the resulting mixture isstirred at 20-25 C. for one hour and then diluted with 100 ml. of water.The solid 2-(2-furoylimino)-5- nitro-4-thiazoline-3-acetamide thatprecipitates is isolated, washed with water and with ether, and dried;m.p. 266 C., following crystallization from acetic acid.

In the foregoing procedure, the same product is obtained when 4.7 g. of2-chloroacetamide is substituted for the 2- bromo-acetamide.

Example 2 To a stirred mixture consisting of 6.0 g. of N-(5-nitro-2-thiazolyl)isonicotinamide, 0.98 g. of a 59 percent sodium hydride inmineral oil dispersion, and 100 ml. of N,N- dimethylformamide is added7.0 g. of 2-bromo-N,N- dipropylacetamide, and the reaction mixture isstirred at 20-25 C. for one hour. It is then diluted with an equalvolume of water, the aqueous mixture is extracted with ethyl acetate,and the ethyl acetate extract is dried and evaporated to give a solidresidue of N-{3-[(di-propylcarbamoyl)methyl]-S-nitro-4-thiazolin-2-ylidene) -isonicotinamide; m.p. l88-l90 C., followingcrystallization from 96 percent ethanol.

The N-(5-nitro-2-thiazolyl)isonicotinamide starting material is obtainedas follows. To a stirred solution of 3.45 g. of 2- amino-S-nitrothiazolein 35 ml. of pyridine at C. is added in portions 5.29 g. of freshlyprepared isonicotinyl chloride hydrochloride and then 20 ml. of acetone.The resulting mixture is stirred for 2 hours at 2025 C. and diluted withan equal volume of water, and the solid N-(-nitro-2-thiazolyl)isonicotinamide that precipitates is isolated, washed withwater, and dried; m.p. 25025l C. (with decomposition), followingcrystallization from ethyl acetate.

Example 3 Utilizing the general procedure described in Examples 1 and 2above, the following 5-nitro-4-thiazoline-3-aceta.mide compounds areobtained from the designated reactants:

a. 2-( 2-Furoylimino )-N,N-dimethyl-5-nitro-4-thiazoline-3- acetamide,m.p. 218.5-220 C. (crystallization from acetic acid); from 12.0 g. ofN-( 5-nitro-2-thiazoyl)-2-furamide, 2.1 g. of a 58 percent sodiumhydride in mineral oil dispersion, and 9.3 g. of2-bromo-N,N-dimethylacetamide.

N,N-Diethyl-2-(2-furoylimino)-5-nitro-4-thiazoline-3- acetarnide, m.p.217-220 C. (acetic acid); from 12.0 g. ofN-(5-nitro-2-thiazoyl)-2-furamide, 2.4 g. of a 50 per cent sodiumhydride in mineral oil dispersion, and 9.7 g. of2-bromo-N,N-diethylacetamide.

c. 2-(Z-Furoylimino)-5-nitro-N,N-dipropyl-4-thiazoline-3- acetamide,m.p. l87-l90 C. (acetic acid); from 12.0 g. ofN-(5-nitro-2-thiazolyl)-2-furamide, 2.4 g. of a 50 percent sodiumhydride in mineral oil dispersion, and 1 1.1 g. of2-bromo-N,N-dipropylacetamide.

d. N-{3-[(Diethylcarbamoyl)methyll-5-nitro-4-thiazolin-2-ylidene}isonicotinamide, m.p. 194-196 C., following successivecrystallizations from ethyl acetate, acetic acid, and 96 percentethanol; from 6.0 g. of N-(5-nitro-2- thiazolyl)isonicotinamide, 1.15 g.of a 50 percent sodium hydride in mineral oil dispersion, and 5.6 g. of2-bromo- N,N-diethylacetarnide.

e. 5-Nitro-2-(2-thenoylimino)-4thiazoline-3-acetamide,

m.p. 270-271 C. (methanol); from 25.5 g. of N-(S-nitro-2-thiazolyl)-2-thiophenecarboxamide, 3.81 g. of a 63 percent sodiumhydride in mineral oil dispersion, and 14.5 g. of 2-bromoacetamide.

f. N,N-Dimethyl-5-nitro-2-(2-thenoylimino) 4-thiazo-line- 3-acetamide,m.p. 250-25l C. (96 percent ethanol); from 12.8 g. ofN-(5-nitro-2-thiazolyl)-2-thiophenecarboxarnide, 2.05 g. of a 58 percentsodium hydride in mineral oil dispersion, and 9.0 g. of 2 -bromo-N,N-dirnethylacetamide. I

g. N,N-Diethyl-5-nitro-2-(2-thenoylimino)-4-thiazoline-3- acetamide,m.p. 20l-202 C. (96 percent ethanol); from 12.8 g. ofN-(5-nitro-2thiazolyl)-2-thiophenecatboxamide, 2.05 g. of a 58 percentsodium hydride in mineral oil dispersion, and 10.0 g. of2-bromo-N,N-diethylacetamide.

h. 5-Nitro-N,N-dipropyl-2-( 2-thenoylimino )-4-thiazo-line- 3-acetamide,m.p. 194l95 C. (96 percent ethanol); from 10.7 g. ofN-(5-nitro-2-thiazolyl)-2-thiophenecarboxamide, 1.71 g. of a 58 percentsodium hydride in mineral oil dispersion, and 10.0 g. of 2bromo-N,N-dipropylacetamide.

i. N-{3-[(Dimethylcarbamoyl)methyl]-5-nitro-4-thiazolin-2-ylidene}isonicotinamide, m.p. 243-245 C. (with decomposition;crystallization from ethanol); from 6.0 g. ofN-(5-nitro-2-thiazolyl)isonicotinamide, 1.15 g. of a 50 percent sodiumhydride in mineral oil dispersion, and 4.7 g. of2-bromo-N,N-dimethylacetamide.

The sulfamate salt of N-{3-[(dimethylcarbamoyl)-methyl]-5-nit.ro-4-thiazolin-Z-ylidene}isonicotinamide is obtained by mixingwarm methanolic solutions of 2.0 g. of the free base and 0.58 g. ofsulfamic acid, chilling the resulting mixture, and isolating and dryingthe solid crystalline salt that is obtained; m.p. 216-22 1 C. (withdecomposition). The sulfate salt, m.p. 240-242C., is obtained in asimilar manner by reacting equivalent quantities of the free base andsulfuric acid.

j. N- {3-[( Dimethylcarbamoyl)methyl]-5nitro-4-thiazolin-2-ylidene}nicotinamide, m.p. 246-247 C. (with decomposition), followingsuccessive crystallizations from aqueous dimethylforrnamide and aceticacid; from 40.0 g. of

' N-(5-nitro-2-thiazolyl)nicotinamide, 5.86 g. of a 66 percent sodiumhydride in mineral oil dispersion, and 29.0 g. of2-bromo-N,N-dimethyl-acetamide.

N- 1' 3 (Dirnethylcarbamoyl )methyl] -5-nitro-4-thiazolin-2-ylidene}picolinamide, m.p. 234236 C. (with decomposition); from 40.0g. of N-(5-nitro-2-thiazolyl)picolinamide, 5.86 g. of a 66 percentsodium hydride in mineral oil dispersion, and 30.0 g. of 2-bromo-N,N-dirnethylacetamide.

The N-(5-nitro-2-thiazolyl)picolinamide starting material is obtained asfollows. To a suspension of 98.4 g. of picolinic acid in 300 ml. oftoluene is added 86.0 g. of thionyl chloride, and the resulting mixtureis heated under reflux for 2.5 hours. Upon cooling. the solution isevaporated under reduced pressure, and the oily residue obtained isadded immediately to a stirred suspension of 87.0 g. ofZ-amino-S-nitrothiazole in 500 ml. of pyridine at such a rate so thatthe temperature of the reaction mixture is kept below 35 C. The mixtureis then stirred for 2 hours at room temperature and poured into water togive a solid precipitate of N-($-nitro-2-thiazolyl)picolinamide, whichis isolated and dried; m.p. 268-274'C. (with decomposition).

lclaim l. A member of the class consisting of 5-nitro-4-thiazoline-3-acetamide compounds having the formula --N-OH A b-N M O OgN V V 7 s N-Rl and pharmaceutically-acceptable acid-addition salts thereof; where Ris a member of theclass consisting of Z-furyl, Z-thienyl, Z-pyridyl,3-pyridyl, and 4-pyridyl, and each of R, and R, is a member of the classconsisting of hydrogen and an alkyl radical containing not more thanthree carbon atoms.

2. A compound according to claim 1 which isZ-(Z-furoylimino)-N,N-dimethyl-5-nitro-4-thiazoline-3-acetamide.

3. A compound according to claim 1 which is N.N-diethyl- 2-(2-furoylirnino)-5-nitro-4-thiazoline-3-acetamide.

4. A compound according to claim 1 which is N-{ 3-[(diethylcarbamoyl)methyl]-5-nitro-4-thiazolin-2-ylidene}-isonicotinamide.

5. A compound according to claim I which is N,N-dimethyl-5-nitro-2-(ZthenoyIimino)-4-thiazoline-3-acetamide.

6. A compound according to claim 1 which is N,N-diethyl- 5-nitro-2-(Z-thenoylimino)-4-thiazoline-3-acetamide.

7. A compound according to claim 1 which is N- {3[(dimethylcarbamoyl)methyl]-5-nitro-4-thiazolin-2-ylidene}- isonicotinamide.

8. A compound according to claim 1 which is apharmaceutically-acceptable acid-addition salt ofN-{3-[(dimethylcarbamoyl)methylJ-S-nitro-4thiazolin-Z-ylidene}-isonicotinamide.

2. A compound according to claim 1 which is2-(2-furoyl-imino)-N,N-dimethyl-5-nitro-4-thiazoline-3-acetamide.
 3. Acompound according to claim 1 which isN,N-diethyl-2-(2-furoylimino)-5-nitro-4-thiazoline-3-acetamide.
 4. Acompound according to claim 1 which isN-(3-((diethylcarbamoyl)methyl)-5-nitro-4-thiazolin-2-ylidene)-isonicotinamide.
 5. A compound according to claim 1 which isN,N-dimethyl-5-nitro-2-(2-thenoylimino)-4-thiazoline-3-acetamide.
 6. Acompound according to claim 1 which isN,N-diethyl-5-nitro-2-(2-thenoylimino)-4-thiazoline-3-acetamide.
 7. Acompound according to claim 1 which isN-(3((dimethylcarbamoyl)methyl)-5-nitro-4-thiazolin-2-ylidene)-isonicotinamide.
 8. A compound according to claim 1 which is apharmaceutically-acceptable acid-addition salt ofN-(3-((dimethylcarbamoyl)methyl)-5-nitro-4thiazolin-2-ylidene)-isonicotinamide.